Guelph-Waterloo Centre for Graduate Studies in Chemistry and Biochemistry, and Department of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, ON, Canada.
Arch Biochem Biophys. 2013 Mar;531(1-2):44-64. doi: 10.1016/j.abb.2012.12.005. Epub 2012 Dec 13.
In nature, proteins most often exist as complexes, with many of these consisting of identical subunits. Understanding of the energetics governing the folding and misfolding of such homooligomeric proteins is central to understanding their function and misfunction, in disease or biotechnology. Much progress has been made in defining the mechanisms and thermodynamics of homooligomeric protein folding. In this review, we outline models as well as calorimetric and spectroscopic methods for characterizing oligomer folding, and describe extensive results obtained for diverse proteins, ranging from dimers to octamers and higher order aggregates. To our knowledge, this area has not been reviewed comprehensively in years, and the collective progress is impressive. The results provide evolutionary insights into the development of subunit interfaces, mechanisms of oligomer folding, and contributions of oligomerization to protein stability, function and regulation. Thermodynamic analyses have also proven valuable for understanding protein misfolding and aggregation mechanisms, suggesting new therapeutic avenues. Successful recent designs of novel, functional proteins demonstrate increased understanding of oligomer folding. Further rigorous analyses using multiple experimental and computational approaches are still required, however, to achieve consistent and accurate prediction of oligomer folding energetics. Modeling the energetics remains challenging but is a promising avenue for future advances.
在自然界中，蛋白质通常以复合物的形式存在，其中许多复合物由相同的亚基组成。了解控制此类同寡聚体蛋白质折叠和错误折叠的能量学对于理解其在疾病或生物技术中的功能和功能障碍至关重要。在定义同寡聚体蛋白质折叠的机制和热力学方面已经取得了很大进展。在这篇综述中，我们概述了用于表征寡聚体折叠的模型以及量热法和光谱学方法，并描述了广泛获得的各种蛋白质的结果，范围从二聚体到八聚体和更高阶聚集体。据我们所知，这个领域多年来没有得到全面综述，而且集体进展令人印象深刻。这些结果为亚基界面的发展、寡聚体折叠的机制以及寡聚化对蛋白质稳定性、功能和调节的贡献提供了进化见解。热力学分析也被证明对理解蛋白质错误折叠和聚集机制很有价值，为新的治疗途径提供了依据。最近成功设计出的新型功能性蛋白质表明，人们对寡聚体折叠的理解有所提高。然而，仍需要使用多种实验和计算方法进行更严格的分析，以实现对寡聚体折叠能量学的一致和准确预测。建模能量学仍然具有挑战性，但这是未来取得进展的一个有前途的途径。
